Biological efficacy of simulated radiolabeled Lipiodol® ultra-fluid and microspheres for various beta emitters: study based on VX2 tumors.

BACKGROUND: Radioembolization is one therapeutic option for the treatment of locally early-stage hepatocellular carcinoma. The aim of this study was to evaluate the distribution of Lipiodol® ultra-fluid and microspheres and to simulate their effectiveness with different beta emitters (90Y, 188Re, 32P, 166Ho, 131I, and 177Lu) on VX2 tumors implanted in the liver of 30 New Zealand rabbits. RESULTS: Twenty-three out of 30 rabbits had exploitable data: 14 in the group that received Lipiodol® ultra-fluid (group L), 6 in the group that received microspheres (group M), and 3 in the control group (group C). The histologic analysis showed that the Lipiodol® ultra-fluid distributes homogeneously in the tumor up to 12 days after injection. The X-ray µCT images showed that Lipiodol® ultra-fluid has a more distal penetration in the tumor than microspheres. The entropy (disorder of the system) in the L group was significantly higher than in the M group (4.06 vs 2.67, p = 0.01). Equivalent uniform biological effective doses (EUBED) for a tumor-absorbed dose of 100 Gy were greater in the L group but without statistical significance except for 177Lu (p = 0.03). The radionuclides ranking by EUBED (from high to low) was 90Y, 188Re, 32P, 166Ho, 131I, and 177Lu. CONCLUSIONS: This study showed a higher ability of Lipiodol® ultra-fluid to penetrate the tumor that translated into a higher EUBED. This study confirms 90Y as a good candidate for radioembolization, although 32P, 166Ho, and 188Re can achieve similar results.

Antitumoral effect of local injection of TLR-9 agonist emulsified in Lipiodol with systemic anti-PD-1 in a murine model of colorectal carcinoma.

Introduction: Local treatments of cancer, including transarterial chemoembolization, could enhance responses to systemic immune checkpoint inhibitors such as anti-PD-1 antibodies. Lipiodol, a radiopaque oil, is widely used for transarterial chemoembolization as a tumor-targeting drug carrier and could be used in emulsion with immunomodulators. This study aimed at evaluating the antitumoral effect of intra-tumoral injection of Lipiodol-immunomodulator emulsions combined with systemic anti-PD-1 therapy in a murine model of colorectal carcinoma. Method: Mice (male BALB/c) with anti-PD-1-resistant subcutaneous CT26 tumors were injected with immunomodulators, emulsified or not with Lipiodol (N=10-12/group). Results: The TLR-9 agonist CpG displayed antitumor effects, while Poly I:C and QS21 did not. The Lipiodol-CpG emulsion appeared to be stable and maintained CpG within tumors for a longer time. Repeated intra-tumoral injections, combined with anti-PD-1, induced responses towards the tumor as well as to a distant metastatic-like nodule. This treatment was associated with an increase in proliferative CD8+ T cells and of IFN-γ expression, a decrease in proliferative regulatory T cells but also, surprisingly, an increase in myeloid derived suppressor cells. Conclusions: Local administration of CpG emulsified with Lipiodol led to an effective antitumoral effect when combined to systemic anti-PD-1 therapy. Lipiodol, apart from its radiopaque properties, is an efficient drug-delivery system. The formulated oil-in-water emulsion allows efficient loading and control release of CpG, which induces favorable immune modifications in this murine tumor model.

Small Brain Lesion Enhancement and Gadolinium Deposition in the Rat Brain: Comparison Between Gadopiclenol and Gadobenate Dimeglumine.

OBJECTIVES: The aim of the set of studies was to compare gadopiclenol, a new high relaxivity gadolinium (Gd)-based contrast agent (GBCA) to gadobenate dimeglumine in terms of small brain lesion enhancement and Gd retention, including T1 enhancement in the cerebellum. MATERIALS AND METHODS: In a first study, T1 enhancement at 0.1 mmol/kg body weight (bw) of gadopiclenol or gadobenate dimeglumine was evaluated in a small brain lesions rat model at 2.35 T. The 2 GBCAs were injected in an alternated and cross-over manner separated by an interval of 4.4 ± 1.0 hours (minimum, 3.5 hours; maximum, 6.1 hours; n = 6). In a second study, the passage of the GBCAs into cerebrospinal fluid (CSF) was evaluated by measuring the fourth ventricle T1 enhancement in healthy rats at 4.7 T over 23 minutes after a single intravenous (IV) injection of 1.2 mmol/kg bw of gadopiclenol or gadobenate dimeglumine (n = 6/group). In a third study, Gd retention at 1 month was evaluated in healthy rats who had received 20 IV injections of 1 of the 2 GBCAs (0.6 mmol/kg bw) or a similar volume of saline (n = 10/group) over 5 weeks. T1 enhancement of the deep cerebellar nuclei (DCN) was assessed by T1-weighted magnetic resonance imaging at 2.35 T, performed before the injection and thereafter once a week up to 1 month after the last injection. Elemental Gd levels in central nervous system structures, in muscle and in plasma were determined by inductively coupled plasma mass spectrometry (ICP-MS) 1 month after the last injection. RESULTS: The first study in a small brain lesion rat model showed a ≈2-fold higher number of enhanced voxels in lesions with gadopiclenol compared with gadobenate dimeglumine. T1 enhancement of the fourth ventricle was observed in the first minutes after a single IV injection of gadopiclenol or gadobenate dimeglumine (study 2), resulting, in the case of gadopiclenol, in transient enhancement during the injection period of the repeated administrations study (study 3). In terms of Gd retention, T1 enhancement of the DCN was noted in the gadobenate dimeglumine group during the month after the injection period. No such enhancement of the DCN was observed in the gadopiclenol group. Gadolinium concentrations 1 month after the injection period in the gadopiclenol group were slightly increased in plasma and lower by a factor of 2 to 3 in the CNS structures and muscles, compared with gadobenate dimeglumine. CONCLUSIONS: In the small brain lesion rat model, gadopiclenol provides significantly higher enhancement of brain lesions compared with gadobentate dimeglumine at the same dose. After repeated IV injections, as expected for a macrocyclic GBCA, Gd retention is minimalized in the case of gadopiclenol compared with gadobenate dimeglumine, resulting in no T1 hypersignal in the DCN.

One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model.

Purpose To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents gadodiamide (a linear contrast agent) or gadoterate (a macrocyclic contrast agent). Materials and Methods Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI (n = 140 rats, corresponding to seven time points, two contrast agents, and 10 rats per group). Animals were sacrificed at 1 week, 1 month, and 2, 3, 4, 5, and 12 months after the last injection. Brain and plasma were sampled to determine the total gadolinium concentration by using inductively coupled plasma mass spectrometry (ICP-MS). For the cerebellum, gadolinium speciation analysis was performed after mild extraction at four time points (1 month and 3, 5, and 12 months after the last injection) by using size exclusion chromatography and hydrophilic interaction liquid chromatography, both coupled to ICP-MS. Tissue gadolinium kinetics were fitted to estimate the area under the curves and tissue elimination half-lives over the 12-month injection-free period. Results T1 hyperintensity of the deep cerebellar nuclei was observed only in gadodiamide-treated rats and remained stable from the 1st month after the last injection (the ratio of the signal intensity of the deep cerebellar nuclei to the signal intensity of the brain stem at 1 year: 1.101 ± 0.023 vs 1.037 ± 0.022 before injection, P < .001). Seventy-five percent of the total gadolinium detected after the last injection of gadodiamide (3.25 nmol/g ± 0.30) was retained in the cerebellum at 1 year (2.45 nmol/g ± 0.35), with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with gadoterate, consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels (0.07 nmol/g ± 0.03). Conclusion After repeated administration of gadodiamide, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of gadoterate, only traces of the intact chelated gadolinium were observed with time-dependent clearance. Online supplemental material is available for this article.

USPIO (Ferumoxtran-10)-enhanced MRI to visualize reticuloendothelial system cells in neonatal rats: feasibility and biodistribution study.

PURPOSE: To investigate whether USPIO-enhanced magnetic resonance imaging (MRI) detected reticuloendothelial system (RES) cells in newborn normal rats. MATERIALS AND METHODS: Newborn normal rats were imaged in vivo on a 1.5 T MR system, 2-96 hours after intraperitoneal Ferumoxtran-10 (n = 38) or saline injection (control group, n = 5). Signals from liver, spleen, and vertebral bone marrow were measured (T2-weighted Turbo Spin Echo) to describe the kinetics of enhancement. The pups were sacrificed and iron concentrations in plasma and peritoneal fluid were measured using atomic absorption spectrometry. Prussian blue-labeled cells density in liver, spleen, and vertebral bone marrow was assessed. RESULTS: Significant (P < 0.05) negative enhancement of the liver, spleen, and vertebral bone marrow was noted after Ferumoxtran-10 injection (2-96 hours for liver and spleen, 4-96 hours for bone marrow). Ferumoxtran-10 was absorbed from the peritoneum in the first 8 hours postinjection, entering the circulation with a plasma peak (8 hours); then Ferumoxtran-10 returned over the baseline in plasma (96 hours). Important intracellular iron deposition in liver and spleen was measured postinjection (3-96 hours, P < 0.05). Limited but significant intracellular iron deposition was noted in vertebral bone marrow postinjection (96 hours, P < 0.05), suggesting that Ferumoxtran-10 selectively labeled RES cells after 96 hours and produced nonspecific labeling at earlier timepoints. CONCLUSION: Ferumoxtran-10-enhanced MRI visualizes RES cells in vivo in newborn rats.

Magnetic susceptibility matching at the air-tissue interface in rat lung by using a superparamagnetic intravascular contrast agent: influence on transverse relaxation time of hyperpolarized helium-3.

Transverse relaxation of hyperpolarized helium-3 magnetization in respiratory airways highly depends on local magnetic field gradients induced by the magnetic susceptibility difference between gas and pulmonary tissue. Fast transverse relaxation is known to be an important feature that yields information about lung microstructure and function, but it is also an essential limitation in designing efficient strategies for lung imaging. Using intravascular injections of a superparamagnetic contrast agent in rats, it was possible to increase the overall susceptibility of the perfused lung tissues and hence to match it with the gas susceptibility. The transverse decay time constant of inhaled hyperpolarized helium-3 was measured in multiple-spin-echo experiments at 1.5 T as a function of the superparamagnetic contrast agent concentration in the animal blood. The time constant was increased by a factor of 3 when an optimal concentration was reached as predicted for susceptibility matching by combining intrinsic susceptibilities of tissue, blood, and gas.

Optimization of a blood pool contrast agent injection protocol for MR angiography.

PURPOSE: To design an ideal first-pass profile for MR angiography (MRA) by optimizing a multiphasic injection protocol based on two experimental animal models. MATERIALS AND METHODS: An equivalent contrast-enhanced (CE) MRA injection protocol was developed with controlled injection modalities (injection rate, volume, and dose) in rabbits and pigs. P792, a blood pool contrast agent, was injected in 17 male New Zealand rabbits and five farm pigs with variable injection schemes (mono- and multiphasic). From the gadolinium (Gd) blood concentration data, a simulation of an MR acquisition was performed to evaluate the impact of such an injection protocol on MR arterial signal and to select the best injection protocol. RESULTS: An empirical relationship between the arterial peak concentration and the injection parameters was found in the rabbits and pigs, allowing precise prediction of the first-pass profile. Of the four injection scheme strategies tested (standard bolus and bi-, tri-, and multiphasic injection protocols), the multiphasic "ramp" injection protocol provided the most optimal contrast agent pharmacokinetics with a durable plateau of concentration. CONCLUSION: Ramp injection protocol provides an optimized first-pass profile for CE-MRA.

Effects of two dimeric iodinated contrast media on renal medullary blood perfusion and oxygenation in dogs.

RATIONALE AND OBJECTIVES: To compare the effects of two iodinated contrast media, iodixanol and ioxaglate, on outer medullary blood flow (MBF) and oxygen tension (MPO(2)) in the dog kidney. METHODS: Iodixanol and ioxaglate were injected selectively into the renal artery (320 mgI/kg) of anesthetized Beagle dogs. MBF and MPO(2) were measured with a laser-Doppler probe and an oxygen-sensing microelectrode implanted in the outer medulla. Urine samples were collected for viscosity and osmolality measurements. RESULTS: Both contrast media produced a moderate decrease in MBF and MPO(2). The hypoperfusion and hypoxia lasted significantly longer with iodixanol than with ioxaglate. Theophylline, an adenosine receptor antagonist, partially prevented iodixanol-induced hypoxia. Urine viscosity was dramatically increased by iodixanol but not by ioxaglate. Urine osmolality did not differ significantly between groups. CONCLUSION: Iodixanol produced a more sustained medullary hypoxia than ioxaglate when injected selectively into the dog renal artery. This may lead to hypoxic cellular damage and subsequent impairment of kidney functions.